scholarly journals Humoral immunity is the dominant barrier for allogeneic bone marrow engraftment in sensitized recipients

Blood ◽  
2006 ◽  
Vol 108 (10) ◽  
pp. 3611-3619 ◽  
Author(s):  
Hong Xu ◽  
Paula M. Chilton ◽  
Michael K. Tanner ◽  
Yiming Huang ◽  
Carrie L. Schanie ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Humoral Immunity ◽  
Bone Marrow Cells ◽  
Critical Role ◽  
Cell Mediated Immunity ◽  
Allogeneic Bone ◽  
Donor Skin

Abstract We evaluated the relative contribution of the humoral and cellular arms of the immune response to bone marrow cells transplanted into sensitized recipients. We report here for the first time that humoral immunity contributes predominantly to allosensitization. Although the major role for nonmyeloablative conditioning is to control alloreactive host T cells in nonsensitized recipients, strikingly, none of the strategies directed primarily at T-cell alloreactivity enhanced engraftment in sensitized mice. In evaluating the mechanism behind this barrier, we found that humoral immunity plays a critical role in the rejection of allogeneic marrow in sensitized recipients. Adoptive transfer of as little as 25 μL serum from sensitized mice abrogated engraftment in secondary naive recipients. With the use of μMT mice as recipients, we found that T-cell-mediated immunity plays a secondary but still significant role in allorejection. Targeting of T cells in sensitized B-cell-deficient μMT mice enhanced alloengraftment. Moreover, both T- and B-cell tolerance were achieved in sensitized recipients when allochimerism was established, as evidenced by the acceptance of second donor skin grafts and loss of circulating donor-specific Abs. These findings have important implications for the management of sensitized transplant recipients and for xenotransplantation in which B-cell reactivity is a predominant barrier.

scholarly journals Impaired bone marrow B-cell development in mice with a bronchiolitis obliterans model of cGVHD

2018 ◽  
Vol 2 (18) ◽  
pp. 2307-2319 ◽  
Author(s):  
Oleg V. Kolupaev ◽  
Trisha A. Dant ◽  
Hemamalini Bommiasamy ◽  
Danny W. Bruce ◽  
Kenneth A. Fowler ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Bronchiolitis Obliterans ◽  
Critical Role ◽  
Cell Development ◽  
B Cell Development ◽  
Allogeneic Bone ◽  
B Cell Precursors

Abstract Chronic graft-versus-host disease (cGVHD) causes significant morbidity and mortality in patients after allogeneic bone marrow (BM) or stem cell transplantation (allo-SCT). Recent work has indicated that both T and B lymphocytes play an important role in the pathophysiology of cGVHD. Previously, our group showed a critical role for the germinal center response in the function of B cells using a bronchiolitis obliterans (BO) model of cGVHD. Here, we demonstrated for the first time that cGVHD is associated with severe defects in the generation of BM B lymphoid and uncommitted common lymphoid progenitor cells. We found an increase in the number of donor CD4+ T cells in the BM of mice with cGVHD that was negatively correlated with B-cell development and the frequency of osteoblasts and Prrx-1–expressing perivascular stromal cells, which are present in the B-cell niche. Use of anti-DR3 monoclonal antibodies to enhance the number of donor regulatory T cells (Tregs) in the donor T-cell inoculum ameliorated the pathology associated with BO in this model. This correlated with an increased number of endosteal osteoblastic cells and significantly improved the generation of B-cell precursors in the BM after allo-SCT. Our work indicates that donor Tregs play a critical role in preserving the generation of B-cell precursors in the BM after allo-SCT. Approaches to enhance the number and/or function of donor Tregs that do not enhance conventional T-cell activity may be important to decrease the incidence and severity of cGVHD in part through normal B-cell lymphopoiesis.

Recipient CD8+ DC Delete Alloreactive Donor CTL and Promote Leukemic Relapse after Allogeneic BMT

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4279-4279
Author(s):  
Kate A Markey ◽  
Rachel D Kuns ◽  
Renee J Robb ◽  
Motoko Koyama ◽  
Kate Helen Gartlan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
Median Survival ◽  
Conflicts Of Interest ◽  
Critical Role ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Leukemic Relapse

Abstract Allogeneic bone marrow transplantation (BMT) remains the therapy of choice for many haematological malignancies, but despite the curative benefit of the immunological graft-versus-leukemia (GVL) effect, relapse remains a key cause of death. We have investigated the role of recipient dendritic cells (DC) in antigen presentation to donor CD8 cytotoxic T cells (CTL) in a model of BMT where GVHD and GVL are directed to multiple minor histocompatibility antigens (mHA) and survival reflects GVL activity. C3H.Sw bone marrow and purified CD8 T cell grafts were transplanted with B6-derived MLL-AF9 induced primary acute myeloid leukemia (AML) into lethally irradiated B6.CD11c.DOG recipients (diphtheria toxin receptor (DTR), ovalbumin and GFP expression driven off the CD11c promoter) such that recipient DC can be deleted by DT administration. Surprisingly, depletion of recipient DC resulted in improved leukemic control (median survival 43 vs 31 days, P <0.001). The use of IRF8-/- BMT recipients (in which the CD8+ DC subset is absent) confirmed that recipient CD8+ DC were critical for regulating these GVL effects (median survival 43 vs 34 days, P = 0.0005). Conversely, when recipient CD8+ DC were expanded in a B6 to B6D2F1 model with bcr-abl/Nup98-HoxA9 induced primary AML, by using Flt3-L treatment for 10 days prior to BMT, GVL effects were completely eliminated, rendering relapse rate equivalent to that seen in the recipients of T cell depleted (TCD) grafts (median survival 11 days in BM+T and TCD groups where recipients were pre-treated with Flt3-L, vs. >45 days in the saline treated BM+T group). The use of B6.CD11c-Rac1 transgenic BMT recipients (who cannot process and present exogenously acquired antigen) confirmed that this effect was the result of endogenous alloantigen presentation by recipient DC and independent of cross-presentation.Using the same depletion strategies in an antigen-specific model (with donor OT-I T cells and B6.CD11c.DOG x DBA/2 F1 recipients) we confirmed that recipient DC invoked effector donor CTL activation, differentiation (CD25+ CD69+ CD62L-) and subsequent apoptosis (as measured by Annexin V; 52.4% vs. 23.9% in DC replete vs. depleted recipients, P = 0.01). There was a consequent profound contraction of the donor CTL compartment by day 10 in DC replete recipients. This contraction of the CTL compartment was associated with reduced expression of the cytolytic molecule granzyme B (MFI 1922 vs 1097, P = 0.02). Antigen presentation has a critical role in the initiation of donor T cell alloreactivity and GVL after BMT. Here we demonstrate that endogenous alloantigen presentation by recipient CD8+ DC to donor T cells leads to activation induced death of donor CTL early after BMT, which in turn facilitates leukemic relapse. This concept has critical implications for the design of therapies that target DC in the peri-transplant period and confirms that recipient DC regulate GVL effects. Disclosures No relevant conflicts of interest to declare.

Abnormal T cell–dependent B-cell responses in SCID mice receiving allogeneic bone marrow in utero

Blood ◽  
2002 ◽  
Vol 100 (13) ◽  
pp. 4557-4564 ◽  
Author(s):  
Thomas J. Waldschmidt ◽  
Angela Panoskaltsis-Mortari ◽  
Ronald T. McElmurry ◽  
Lorraine T. Tygrett ◽  
Patricia A. Taylor ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Humoral Immunity ◽  
In Utero ◽  
Scid Mice ◽  
Cell Transplant ◽  
Allogeneic Bone ◽  
B Cell Subsets

In allogeneic hematopoietic stem cell transplant recipients, restoration of humoral immunity is delayed and can remain impaired for years. In many severe combined immune deficiency (SCID) patients given haploidentical bone marrow (BM), lesions in humoral immunity are exacerbated by poor engraftment of donor B cells. The nature of these defects is important to understand as they render patients susceptible to infection. Previous work in mice suggested that in utero transplantation (IUT) of allogeneic BM might offer several advantages for the correction of primary immune deficiencies. In SCID mice given fully allogeneic BM in utero, the lymphoid compartment was restored with minimal evidence of graft-versus-host disease (GVHD). The present report examines B-cell reconstitution and function in mice that have received allogeneic IUT. Results are compared with those of adult mice given total body irradiation (TBI) followed by transplantation with allogeneic BM. In addition to enumerating the various B-cell subsets present in BM, spleen, and peritoneal cavity (PC), B-cell competence was assessed by challenging mice with T cell–independent (TI) and T cell–dependent (TD) antigens. The results demonstrated that all B-cell subsets in the BM and periphery were restored in allogeneic IUT and TBI mice, as were antibody responses after TI challenge. Upon immunization with TD antigens, however, IUT and TBI mice exhibited suboptimal responses as measured by the capacity to isotype switch and generate germinal center (GC) B cells. Thus, although allogeneic BM transplantation results in complete recovery of the B-cell compartment, certain elements of the humoral response remain defective.

Allogeneic bone marrow cells that facilitate complete chimerism and eliminate tumor cells express both CD8 and T-cell antigen receptor–αβ

Blood ◽  
2001 ◽  
Vol 97 (11) ◽  
pp. 3458-3465 ◽  
Author(s):  
Fengshuo Lan ◽  
Defu Zeng ◽  
Philip Huie ◽  
John P. Higgins ◽  
Samuel Strober
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Bone Marrow Cells ◽  
Antigen Receptor ◽  
Allogeneic Bone Marrow ◽  
Allogeneic Bone ◽  
Cell Antigen Receptor ◽  
Cell Antigen

Nonmyeloablative host conditioning regimens have been used in clinical allogeneic bone marrow and hematopoietic progenitor transplantation to effectively treat lymphohematopoietic tumors and reduce early toxicity. However, severe graft-versus-host disease (GVHD) remains a major problem. The goal of the current study was to determine whether specific subsets of cells in allogeneic bone marrow transplants can effectively treat the BCL1 B-cell lymphoma in nonmyeloablated BALB/c mouse hosts given a single dose of sublethal (450 cGy) total body irradiation, without inducing severe GVHD. The experimental results show that high doses of whole bone marrow cells from major histocompatiblity complex (MHC)-mismatched donors eliminate both normal and malignant host-type lymphohematopoietic cells without causing injury to nonlymphohematopoietic host tissues. The CD8+T-cell antigen receptor–αβ+(TCRαβ+) T cells within the marrow transplants mediated the killing of the tumor cells via both perforin- and FasL-dependent pathways. Cells present in marrow transplants from either CD8−/− or TCRα−/− donors failed to eliminate malignant and normal host lymphohematopoietic cells. Addition of small numbers of blood mononuclear cells to the marrow inoculum caused lethal GVHD. Thus, the resident allogeneic bone marrow CD8+ TCRαβ+ T cells had the unique capacity to eliminate the host lymphohematopoietic cells without nonlymphohematopoietic tissue injury.

In the Absence of Preformed Antibody, Sensitized T Cells Mediate an Increased Barrier to Engraftment.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 191-191
Author(s):  
Hong Xu ◽  
Paula M. Chilton ◽  
Yiming Huang ◽  
Carrie L. Schanie ◽  
Michael K. Tanner ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Humoral Immunity ◽  
Graft Rejection ◽  
Bone Marrow Cells ◽  
Skin Grafts ◽  
Relative Contribution ◽  
Marrow Cells

Abstract Allosensitization resulting from transfusion therapy is a major challenge for the use of bone marrow transplantation to treat sickle cell disease. Prior exposure to foreign major histocompatibility complex (MHC) antigens through transfusion or transplantation is associated with an increased rate of solid organ graft rejection. Using a mouse model for sensitization, we recently found that humoral immunity plays a dominant role in sensitization to MHC alloantigens and concomitant graft rejection. The relative contribution of cellular versus humoral adaptive immune responses has not been fully characterized. In this study, we explored the role of host T cells in rejection of allografts by sensitized recipients using μ MT mice which are defective in producing mature B cells and antibody. Therefore, the barrier from preformed antibodies in sensitized normal mice would not exist in μ MT mice. μ MT (H-2b) mice were sensitized with BALB/c (H-2d) skin grafts. Although no anti-MHC alloantibody was detected in the μ MT mice after rejection, the skin grafts were rejected with a kinetic similar to normal controls (MST = 14.1 ± 1.2 days versus 13.6 ± 1.5 days). The prompt rejection of skin allografts by B cell deficient mice suggests that T cell activation and function are normal in vivo and that T cells alone are sufficient to reject allogeneic skin grafts. BMT was subsequently performed in presensitized μ MT mice 5 weeks after sensitization as well as in naïve μ MT mice. All naïve μ MT mice (n = 6) engrafted with 700 cGy TBI and 30 x 106 bone marrow cells, but none of the presensitized μ MT mice engrafted. Since humoral immunity is absent in sensitized μ MT mice, the increased barrier in these mice therefore must be mediated by the primed T cells. To further define the relative contribution of T cell subpopulations to alloresistance, we targeted these populations in vivo as preconditioning using monoclonal antibodies (mAb). Sensitized μ MT mice were treated with anti-α β-TCR, anti-CD8, anti-CD4 or anti-CD154 mAbs alone or in combination and 850 cGy of total body irradiation, then transplanted with untreated BALB/c donor bone marrow cells (Figure). Engraftment did not occur in the sensitized μ MT mice without mAb treatment, while nearly all animals engrafted with preconditioning with anti-α β-TCR alone, anti-CD8 plus anti-CD154, or anti-CD8 plus anti-CD4 (100%, 87.5%, and 100% respectively) and transplantation with 30 x 106 donor BM cells. Moreover, anti-α β-TCR preconditioning promoted engraftment in all sensitized μ MT mice with transplantation of as low as 15 x 106 BM cells. These data demonstrate that T cell mediated cellular immunity contributes to rejection in sensitized recipients, and that successful therapies to achieve allogeneic engraftment using nonmyeloablative conditioning in sensitized recipients will need to address both arms of the adaptive antigen-specific immune system: cellular and humoral. Figure Figure

Quantitative assays for detection of residual T cells of T-depleted human marrow

Blood ◽  
1985 ◽  
Vol 65 (5) ◽  
pp. 1134-1140 ◽  
Author(s):  
PJ Martin ◽  
JA Hansen
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Indirect Immunofluorescence ◽  
Bone Marrow Cells ◽  
Allogeneic Bone ◽  
Dilution Assay ◽  
Limiting Dilution Assay ◽  
Limiting Dilution ◽  
Marrow Cells

Preliminary studies have suggested that depletion of T lymphocytes from donor marrow might be an effective method for preventing acute graft-v- host disease (GVHD) after allogeneic bone marrow transplantation in humans (Lancet 1:369, 472, 1984). However, the minimum degree of T cell depletion required to assure the prevention of GVHD in a population of marrow graft recipients has not been defined, largely because quantitative assays with sufficient sensitivity for detecting small numbers of residual viable T cells have not been developed. We have investigated three methods for the detection and enumeration of T cells after treatment of bone marrow with murine monoclonal anti-T cell antibodies and complement. Cell populations prepared by adding graded numbers of T cells to treated bone marrow were analyzed by immediate indirect immunofluorescence, by indirect immunofluorescence after culture of cells in medium containing phytohemagglutinin (PHA), or by a limiting-dilution assay. Immediate indirect immunofluorescence could reliably detect 300 T cells per 10(5) treated bone marrow cells. Indirect immunofluorescence after culture in PHA was tenfold more sensitive and could reliably detect 30 T cells per 10(5) treated bone marrow cells. The limiting dilution assay could be 300-fold more sensitive than immediate indirect immunofluorescence and 30-fold more sensitive than indirect immunofluorescence after culture in PHA. Sensitive, quantitative assays will be useful in guiding the development of methods for efficient removal of T cells in donor marrow, and will be essential for monitoring and interpreting the results of clinical trials.

scholarly journals Quantitative assays for detection of residual T cells of T-depleted human marrow

Blood ◽  
1985 ◽  
Vol 65 (5) ◽  
pp. 1134-1140 ◽  
Author(s):  
PJ Martin ◽  
JA Hansen
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Indirect Immunofluorescence ◽  
Bone Marrow Cells ◽  
Allogeneic Bone ◽  
Dilution Assay ◽  
Limiting Dilution Assay ◽  
Limiting Dilution ◽  
Marrow Cells

Abstract Preliminary studies have suggested that depletion of T lymphocytes from donor marrow might be an effective method for preventing acute graft-v- host disease (GVHD) after allogeneic bone marrow transplantation in humans (Lancet 1:369, 472, 1984). However, the minimum degree of T cell depletion required to assure the prevention of GVHD in a population of marrow graft recipients has not been defined, largely because quantitative assays with sufficient sensitivity for detecting small numbers of residual viable T cells have not been developed. We have investigated three methods for the detection and enumeration of T cells after treatment of bone marrow with murine monoclonal anti-T cell antibodies and complement. Cell populations prepared by adding graded numbers of T cells to treated bone marrow were analyzed by immediate indirect immunofluorescence, by indirect immunofluorescence after culture of cells in medium containing phytohemagglutinin (PHA), or by a limiting-dilution assay. Immediate indirect immunofluorescence could reliably detect 300 T cells per 10(5) treated bone marrow cells. Indirect immunofluorescence after culture in PHA was tenfold more sensitive and could reliably detect 30 T cells per 10(5) treated bone marrow cells. The limiting dilution assay could be 300-fold more sensitive than immediate indirect immunofluorescence and 30-fold more sensitive than indirect immunofluorescence after culture in PHA. Sensitive, quantitative assays will be useful in guiding the development of methods for efficient removal of T cells in donor marrow, and will be essential for monitoring and interpreting the results of clinical trials.

scholarly journals Keratinocyte growth factor enhances DNA plasmid tumor vaccine responses after murine allogeneic bone marrow transplantation

Blood ◽  
2009 ◽  
Vol 113 (7) ◽  
pp. 1574-1580 ◽  
Author(s):  
Robert R. Jenq ◽  
Christopher G. King ◽  
Christine Volk ◽  
David Suh ◽  
Odette M. Smith ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Keratinocyte Growth Factor ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Effector Cells ◽  
Cd8 Cells ◽  
T Cell Reconstitution ◽  
Dna Plasmid

Abstract Keratinocyte growth factor (KGF), which is given exogenously to allogeneic bone marrow transplantation (allo-BMT) recipients, supports thymic epithelial cells and increases thymic output of naive T cells. Here, we demonstrate that this improved T-cell reconstitution leads to enhanced responses to DNA plasmid tumor vaccination. Tumor-bearing mice treated with KGF and DNA vaccination have improved long-term survival and decreased tumor burden after allo-BMT. When assayed before vaccination, KGF-treated allo-BMT recipients have increased numbers of peripheral T cells, including CD8+ T cells with vaccine-recognition potential. In response to vaccination, KGF-treated allo-BMT recipients, compared with control subjects, generate increased numbers of tumor-specific CD8+ cells, as well as increased numbers of CD8+ cells producing interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). We also found unanticipated benefits to antitumor immunity with the administration of KGF. KGF-treated allo-BMT recipients have an improved ratio of T effector cells to regulatory T cells, a larger fraction of effector cells that display a central memory phenotype, and effector cells that are derived from a broader T-cell–receptor repertoire. In conclusion, our data suggest that KGF can function as a potent vaccine adjuvant after allo-BMT through its effects on posttransplantation T-cell reconstitution.

scholarly journals Keratinocyte growth factor (KGF) is required for postnatal thymic regeneration

Blood ◽  
2006 ◽  
Vol 107 (6) ◽  
pp. 2453-2460 ◽  
Author(s):  
Önder Alpdogan ◽  
Vanessa M. Hubbard ◽  
Odette M. Smith ◽  
Neel Patel ◽  
Sydney Lu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Growth Factor ◽  
Keratinocyte Growth Factor ◽  
Critical Role ◽  
T Cell Development ◽  
Marrow Transplant ◽  
Cell Development ◽  
Allogeneic Bone ◽  
Thymic Regeneration

AbstractKeratinocyte growth factor (KGF) is a member of the fibroblast growth factor family that mediates epithelial cell proliferation and differentiation in a variety of tissues, including the thymus. We studied the role of KGF in T-cell development with KGF-/- mice and demonstrated that thymic cellularity and the distribution of thymocyte subsets among KGF-/-, wildtype (WT), and KGF+/- mice were similar. However, KGF-/- mice are more vulnerable to sublethal irradiation (450 cGy), and a significant decrease was found in thymic cellularity after irradiation. Defective thymopoiesis and peripheral T-cell reconstitution were found in KGF-/- recipients of syngeneic or allogeneic bone marrow transplant, but using KGF-/- mice as a donor did not affect T-cell development after transplantation. Despite causing an early developmental block in the thymus, administration of KGF to young and old mice enhanced thymopoiesis. Exogenous KGF also accelerated thymic recovery after irradiation, cyclophosphamide, and dexamethasone treatment. Finally, we found that administering KGF before bone marrow transplantation (BMT) resulted in enhanced thymopoiesis and peripheral T-cell numbers in middle-aged recipients of an allogeneic BM transplant. We conclude that KGF plays a critical role in postnatal thymic regeneration and may be useful in treating immune deficiency conditions. (Blood. 2006;107:2453-2460)

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